The aim of this project is to gain a greater understanding of the psychobiology of schizophrenia and to develop improved strategies for its treatment. An important goal is the understanding of the mechanisms of action of neuroleptic drugs. We have observed that neuroleptic-induced time-dependent decrease in levels of plasma homovanillic acid (HVA), a major dopamine metabolite, correlates with antipsychotic drug response, suggesting that slow to develop changes in dopamine turnover may underlie the antipsychotic action of neuroleptics. The origin of this clinically relevant HVA "signal" (peripheral or central CNS) is being investigated by a strategy in which peripherally derived HVA is reduced by the administration of debrisoquin, a MAO inhibitor which does not enter the CNS. In a double-blind, treatment trial, we have observed significant reduction in psychosis when alprazolam is added to neuroleptic treatment. These data contrast with the negative results found when the calcium channel blocker, verapamil, was administered to otherwise medication-free schizophrenic patients. In studies using computerized tomography imaging techniques, findings continue to support structural abnormality in the prefrontal cortex of schizophrenic patients. Magnetic resonance imaging (MRI) techniques are currently being employed to pursue structural abnormalities in brains of schizophrenic patients. The proposed course of study highlights the pharmacotherapy of schizophrenia, including the use of levels of plasma HVA as a marker for antipsychotic response and the augmentation of neuroleptic response using triazolobenzodiazepines.